Evaluation of Intracoronary AB-1002 Efficacy and Safety in NYHA Class III Non-Ischemic Cardiomyopathy
- Trial ID
- 2024-510581-17-00
- Protocol
- ASK-CHF2-CS201
- Sponsor
- Askbio Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to **evaluate** the efficacy and safety of a single antegrade intracoronary artery infusion of **AB-1002** compared to placebo in subjects with non-ischemic cardiomyopathy and New York Heart Association (NYHA) Class III symptoms of heart failure. This is clinically relevant as it aims to determine the potential therapeutic benefits and safety profile of AB-1002, a novel gene therapy, in improving cardiac function and managing symptoms in this patient population.
Secondary objectives include evaluating the impact of AB-1002 on cardiac function, exercise capacity, quality of life (QOL), and cardiac biomarkers, specifically the levels of N-terminal pro-hormone b-type natriuretic peptide (NT-proBNP). These assessments are crucial for understanding the broader effects of the treatment on patients' overall health and well-being, as well as its potential to improve clinical outcomes in heart failure management.
Participants
The clinical trial involves a total of **80 participants** diagnosed with **New York Heart Association (NYHA) Class III congestive heart failure** and **non-ischemic cardiomyopathy**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including a left ventricular ejection fraction (LVEF) between 15% and 35% as determined by transthoracic echocardiography, and the ability to walk more than 50 meters in a six-minute walk test. All subjects are required to be medically stable with NYHA Class III heart failure for at least four weeks while on appropriate medical therapy. The trial population is characterized by a medically stable condition, with participants having maintained stable doses of heart failure medications for at least 30 days prior to enrollment. Lifestyle considerations include the use of highly effective birth control methods for women of childbearing potential and the agreement of male participants to not donate sperm for six months post-intervention. The trial does not exclude any gender and includes a vulnerable population, ensuring a comprehensive evaluation of the investigational treatment's efficacy and safety.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled, multi-center study to evaluate the efficacy, safety, and tolerability of the investigational product AB-1002 in adult subjects with New York Heart Association (NYHA) Class III **congestive heart failure** and non-ischemic cardiomyopathy. The trial will involve a single antegrade intracoronary artery infusion of AB-1002 compared to a placebo. The study is expected to span a total duration of approximately six years, with an estimated recruitment start date in October 2024 and an estimated end date in October 2030.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, medical history, and current health status. Key inclusion criteria include being 18 years or older, having chronic non-ischemic cardiomyopathy, and a left ventricular ejection fraction (LVEF) between 15% and 35% as determined by transthoracic echocardiography. Following the screening, eligible participants will be randomized to receive either the investigational product or placebo. The primary endpoint will be assessed at 52 weeks, focusing on a modified Win Ratio, which includes hierarchical evaluation of cardiovascular-related death, NYHA classification change, LVEF change, and six-minute walk test (6MWT) change from baseline.
Throughout the trial, participants will attend follow-up visits at specified intervals to monitor safety and efficacy outcomes. These visits will include assessments of treatment-emergent adverse events, changes in clinical laboratory tests, vital signs, and electrocardiograms (ECGs). Secondary endpoints will be evaluated at 24 and 52 weeks, including functional status, hospitalizations, and echocardiographic assessments. The end-of-study visit will mark the conclusion of the participant's involvement, where final evaluations will be conducted.
Participant involvement is expected to last for approximately 52 weeks, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of **AB-1002**, a recombinant AAV2i8 vector, which is a **solution for injection**. This experimental medication is designed to deliver the I-1 inhibitor protein phosphatase under the control of a human cytomegalovirus internal-enhancer promoter, flanked by short inverted terminal repeats sequences. The pharmaceutical form of AB-1002 is a solution for injection, and it is administered via **intracoronary use**. The maximum daily and total dose amount is 143,000,000,000,000.00 units, with a maximum treatment period of one day. The administration of AB-1002 is intended for adult subjects with New York Heart Association (NYHA) Class III heart failure and non-ischemic cardiomyopathy. Participant compliance will be monitored throughout the study to ensure adherence to the dosing schedule.
The study also includes a **placebo** group, which will receive an infusion that mimics the administration of AB-1002 but contains no active substance. The placebo is used to maintain the double-blinded nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is not associated with any specific pharmaceutical form or active substance, and its administration route is consistent with that of the experimental treatment, ensuring comparability between the two groups. The use of a placebo allows for the evaluation of the efficacy and safety of AB-1002 by providing a baseline for comparison.
Efficacy
The efficacy of the investigational product AB-1002 in the clinical trial will be assessed using a primary endpoint known as the Modified Win Ratio at 52 weeks. This endpoint involves a hierarchical evaluation of several assessments, including cardiovascular-related death, changes in New York Heart Association (NYHA) Classification from baseline, changes in left ventricular ejection fraction (LVEF) from baseline, and changes in the six-minute walk test (6MWT) from baseline. The assessments are ordered by priority, with cardiovascular-related death being the most critical.
Secondary endpoints will further evaluate efficacy by examining cardiovascular-related death, functional status, and hospitalizations at 24 and 52 weeks. Additional assessments will include observed values and changes from baseline in NYHA Classification, LVEF, and 6MWT. The number and timing of heart failure (HF) hospitalizations will also be recorded. Physiologic assessments will be conducted, including echocardiographic evaluations of LVEF at weeks 4, 12, and 36, as well as measurements of left ventricular volumes and indices, sphericity index, global longitudinal strain (GLS), and the degree of mitral regurgitation. Cardiac biomarker NT-proBNP levels and patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire (KCCQ) will also be analyzed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject must be age ≥18 years of age, at the time of signing the informed consent
- Chronic non-ischemic cardiomyopathy
- 15% ≤ LVEF ≤ 35% by transthoracic echocardiography (TTE) at screening
- 6MWT >50 meters
- Medically stable, NYHA Class III HF for a minimum of 4 weeks while on appropriate medical therapy (defined below) including, but not limited to: a. Angiotensin-converting enzyme inhibitor (ACE-I), angiotensin receptor-neprilysin inhibitor (ARNI), angiotensin receptor blocker (ARB), sacubitril/valsartan combination therapy (Entresto), beta blocker therapy, mineralocorticoid receptor antagonist (MRA), sodium-glucose co-transporter 2 inhibitor (SGLT2i) for ≥ 90 days prior to enrollment. Doses of the above medications must be stable for ≥ 30 days prior to enrollment. b. Cardiac resynchronization therapy (Zareba et al., 2011), if clinically indicated, must have been implanted ≥ 90 days prior to enrollment. ICD must be implanted, if clinically indicated ≥ 30 days prior to enrollment.
- Women of childbearing potentia (for definition see also Section 9.4.1)l must use at least one of the following highly effective birth control methods throughout the study: - Intrauterine device in place at least 90 days prior receiving SI - Abstinence (the subject must be willing to remain abstinent from screening to 6 months after receiving SI). Females are allowed to claim abstinence as their method of contraception only when it is the preferred and usual lifestyle of the subject - Surgical sterilization of the partner(s) (vasectomy) for >180 days prior to SI administration - Hormonal contraceptives associated with the inhibition of ovulation starting > 90 days prior to SI. If hormonal contraceptives are started less than 90 days prior to receiving SI, subjects must agree to use a barrier method (diaphragm plus spermicide or condom) from screening through 90 days after initiation of hormonal contraceptives
- Males subjects capable of fathering a child: - Must agree not to donate sperm for 6 months (in Belgium: 12 months) after time of receiving SI - Documented evidence of vasectomy in males for 180 days minimum prior to receiving SI is an acceptable form of contraception - Males who claim abstinence as their method of contraception are allowed, provided they agree to use barrier methods should they become sexually active from screening through 6 months (in Belgium: 12 months) after receiving IP. Males are allowed to claim abstinence as their method of contraception only when it is the preferred and usual lifestyle of the subject
- Appropriate candidate for protocol-specified intracoronary infusion in the judgment of the infusing interventional cardiologist
- To protect partners of study subjects from potential viral shedding, sexually active subjects and their partners must agree to use barrier methods of contraception (condoms, female condoms, and dams) for a minimum of 6 months (in Belgium: 12 months) after SI administration; barrier methods should be used regardless of any other applied birth control methods.
Exclusion Criteria
- Chronic ischemic cardiomyopathy secondary to obstructive coronary artery disease
- Intravenous (IV) inotropic therapy, intra-aortic balloon pump (IABP) or percutaneous cardiac assist device therapy within 30 days prior to enrollment
- Restrictive cardiomyopathy, obstructive cardiomyopathy, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease, or dyskinetic LV aneurysm
- Cardiac surgery or PCI within 30 days prior to enrollment
- Uncorrected third degree heart block
- Clinically significant MI in the judgment of the subject’s physician (e.g., ST elevation MI [STEMI] or large non-STEMI) within 6 months prior to enrollment
- Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), surgically implanted LVAD or cardiac shunt
- Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LV reduction surgery, heart transplant, conventional revascularization procedure, or valvular repair within 3 months of SI dosing in the judgment of the investigator
- Known hypersensitivity to contrast dyes (not easily controlled by antihistamines) used for angiography; history of, or likely need for, high dose steroid pretreatment prior to contrast angiography
- known hypersensivity to SI or to any of the exipients or to the placebo
- Expected survival < 1 year in the judgment of the investigator
- Clinicially relevant infection 48 hours prior to intracoronary infusion
- Known intrinsic liver disease (e.g., cirrhosis, hepatitis A, chronic hepatitis B or hepatitis C virus infection). If serology is positive and polymerase chain reaction (PCR) is known to be negative, the subject may be eligible (confirm with medical monitor)
- Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase or total bilirubin) > 2x upper limit of normal (ULN) within 30 days prior to enrollment. In the case that patients have a confirmed diagnosis of benign liver dysfunction (e.g. Gilbert’s syndrome with unconjugated bilirubin not exceeding 4 mg/dL), patients may be eligible for inclusion into the study).
- Chronic Kidney Disease Stage 5, dialysis dependent or eGFR<15 within 30 days prior to enrollment
- Bleeding diathesis or thrombocytopenia defined as platelets <50,000 platelets/μL within 30 days prior to enrollment
- Anemia is defined as hemoglobin <10 g/dL or transfusion dependent within 30 days prior to enrollment
- Neutropenia is defined as absolute neutrophils <1500 mm3 within 30 days prior to enrollment
- Known AIDS or HIV-positive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm3
- Previous participation in a study of gene transfer
- Receiving investigational intervention or participating in another clinical study within 30 days of another investigational drug administration prior to administration of AB-1002 that may impact the therapeutic potential of AB-1002
- Pregnancy or breastfeeding or plans to become pregnant within the next 12 months at the time of screening
- Subjects with any other condition which in the opinion of the investigator would preclude participation in the study (including risk for noncompliance and any intercurrent conditions that pose an undue medical hazard, or which could interfere with the interpretation of the study results)
- Malignant neoplasm within 5 years of dosing, with the exception of those with negligible risk of metastasis or death (such as adequately treated carcinoma in situs of the cervix, basal or squamous cell skin cancer, localized prostate cancer or ductal carcinoma in situ)
- Any documented history of noncompliance with medications; illicit drug use or laboratory evidence of illicit drug use during screen period
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Oct 2024 | 25 |
 Belgium | Not Recruiting | 01 Oct 2024 | 25 |
 Bulgaria | Not Recruiting | 01 Oct 2024 | 30 |
 Germany | Not Recruiting | 01 Oct 2024 | 25 |
 Hungary | Not Recruiting | 01 Oct 2024 | 38 |
 The Netherlands | Not Recruiting | 01 Oct 2024 | — |
 Poland | Not Recruiting | 01 Oct 2024 | 25 |
 Romania | Not Recruiting | 01 Oct 2024 | 25 |
 Spain | Not Recruiting | 01 Oct 2024 | 25 |
| Netherlands | — | — | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AB-1002 | Test | SOLUTION FOR INJECTION | INTRACORONARY USE | 143000000000000.00 | 1 | PRD10856274 |
AB-1002 Placebo | Placebo | N/A | — | — | — | N/A |